An emerging treatment for Alzheimer's disease (AD) is immunotherapy to clear amyloid-β (Aβ). Another important target in AD and frontotemporal dementia is the neurofibrillary tangles and/or their pathological tau protein conformers, whose presence correlates well with the degree of dementia (Terry, R., “Neuropathological Changes in Alzheimer Disease,” Prog Brain Res. 101:383-390 (1994); Goedert, M., “Tau Protein and Neurodegeneration,” Semin Cell Dev Biol. 15:45-49 (2004)). The objective of immunotherapy for tau pathology is that anti-tau antibodies can clear tau aggregates that may affect neuronal viability. Tau is a soluble protein that promotes tubulin assembly, microtubule stability, and cytoskeletal integrity. Although tau pathology is likely to occur following Aβ aggregation based on Down syndrome studies, analyses of AD brains and mouse models indicate that these pathologies are likely to be synergistic (Sigurdsson, et al., “Local and Distant Histopathological Effects of Unilateral Amyloid-beta 25-35 Injections into the Amygdala of Young F344 Rats,” Neurobiol Aging 17:893-901 (1996); Sigurdsson, et al., “Bilateral Injections of Amyloid-β 25-35 into the Amygdala of Young Fischer Rats: Behavioral, Neurochemical, and Time Dependent Histopathological Effects,” Neurobiol Aging 18:591-608 (1997); Lewis, et al., “Neurofibrillary Tangles, Amyotrophy and Progressive Motor Disturbance in Mice Expressing Mutant (P301 L) Tau Protein,” Nat Genet. 25:402-405 (2000); Gotz, et al., “Formation of Neurofibrillary Tangles in P301L Tau Transgenic Mice Induced by A-beta 42 Fibrils,” Science 293:1491-1495 (2001); Delacourte, et al., “Nonoverlapping but Synergetic Tau and APP Pathologies in Sporadic Alzheimer's Disease,” Neurology. 59:398-407 (2002); Oddo, ct al., “Abeta Immunotherapy Leads to Clearance of Early, But Not Late, Hyperphosphorylated Tau Aggegates via the Proteasome,” Neuron 43:321-332 (2004)| Ribe, et al., “Accelerated Amyloid Deposition, Neurofibrillary Degeneration and Neuronal Loss in Double Mutant APP/Tau Transgenic Mice,” Neurobiol Dis. (2005)). Hence, targeting both pathologies may substantially increase treatment efficacy. To date, no tau mutations have been observed in AD, however, in frontotemporal dementia, mutations in the tau protein on chromosome 17 (FTDP-17) urea causative factor in the disease, which further supports tau-based therapeutic approaches (Poorkaj, et al., “Tau is a Candidate Gene for Chromosome 17 Frontotemporal Dementia,” Ann Neurol. 43:815-825 (1998); Spillantini, et al., “Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: A New Group of Tauopathies,” Brain Pathol. 8:387-402 (1998)). Transgenic mice expressing these mutations have modeled many aspects of the disease and are valuable tools to study the pathogenesis of tangle-related neurodegeneration and to assess potential therapies. One of these models, the P301L mouse model (Lewis, et al., “Neurofibrillary Tangles, Amyotrophy and Progressive Motor Disturbance in Mice Expressing Mutant (P301L) Tau Protein,” Nat Genet. 25:402-405 (2000)), recapitulates many of the features of frontotemporal dementia although the CNS distribution of the tau aggregates results primarily in sensorimotor abnormalities which complicates cognitive assessment. Homozygous lines of this mouse model have an early onset of CNS pathology and associated functional impairments which make them ideal for the initial assessment of the feasibility, of immunotherapy, targeting pathological tau conformers.
Other tau-related therapeutic approaches include: (1) drugs that inhibit the kinases or activate the phosphatases that affect the state of tau phosphorylation (Iqbal, et al., “Inhibition of Neurofibrillary Degeneration: A Promising Approach to Alzheimer's Disease and Other Tauopathies,” Curr Drug Targets 5:495-502 (2004); Noble, et al., Inhibition of Glycogen Synthase Kinase-3 by Lithium Correlates with Reduced Tauopathy and Degeneration In Vivo,” Proc Nall Acad Sci USA 102:6990-6995 (2005)); (2) microtubule stabilizing drugs (Michaelis, et al., {beta}-Amyloid-Induced Neurodegeneration and Protection by Structurally Diverse Microtubule-Stabilizing Agents,” J Pharmacol Exp Ther. 312:659-668 (2005); Zhang, et al., “Microtubule-Binding Drugs Offset Tau Sequestration by Stabilizing Microtubules and Reversing Fast Axonal Transport Deficits in a Tauopathy Model,” Proc Natl Acad Sci USA 102:227-231 (2005)); (3) compounds that interfere with tau aggregation (Pickhardt, et al., “Anthraquinones Inhibit Tau Aggregation and Dissolve Alzheimer's Paired Helical Filaments In Vitro and in Cells,” J Biol Chem. 280:3628-3635 (2005)); and (4) drugs that promote heat shock protein mediated clearance of tau (Dickey, et al., “Development of a High Throughput Drug Screening Assay for the Detection of Changes in Tau Levels—Proof of Concept with HSP90 Inhibitors,” Curr Alzheimer Res. 2:231-238 (2005)). While all these approaches are certainly worth pursuing, target specificity and toxicity are of a concern, which emphasizes the importance of concurrently developing other types of tau-targeting treatments, such as immunotherapy.
The present invention is directed to overcoming these and other deficiencies in the art.